The recent shift from an overly centrist to a more holistic approach to energy and nutrient homeostasis has emphasized the role of vagal and other visceral afferents involved in gut/brain communication. Vagal sensory fibers are particularly important in relaying satiety signals from the food handling viscera to the brain and therefore play an important role in the control of meal size and possibly overall energy intake. The overall objective of the proposed research is to identify the complete signaling pathway from the periphery to the behavioral action. This includes a) anatomical and neurochemical identification of all participating neuron groups; b) analysis of coding and decoding principles of sensory information; and c) demonstrating how these signals are translated into ingestive and other behavioral actions. While past work mainly focused on anatomical aspects of the peripheral innervation pattern of vagal afferent fibers, the work proposed for this grant focuses on processing of gastrointestinal vagal sensory information in the caudal brainstem. It will test the hypothesis that different nutrients and other peripheral stimuli use anatomically and/or neurochemically separate signaling pathways to the brain. Second order neurons in the caudal brainstem that receive specific sensory signals from the gastrointestinal tract will be identified by complementary anatomical and functional approaches such as transynaptic viral tracing and c-fos induction. Identified neurons will then be characterized as to their neurochemical phenotype by using sensitive in situ hybridization and immunocytochemistry protocols for neurotransmitters, peptides and their receptors. Their axonal projections will be mapped with the use of retrograde tracing. Finally, the involvement of specific transmitters and receptors associated with the sensory vagal pathways in the control of ingestive behavior will be directly tested. In particular, the role of glutamate and its receptor subtypes in the process of satiation of various feeding paradigms will be analyzed by measuring the microstructure of meal taking in computerized monitoring systems for both solid and liquid foods. The research proposal in this application will fill important gaps in our knowledge of neural control of food intake and body weight as well as digestive, absorptive and defense mechanisms of the gastrointestinal tract. It has therefore, the potential to spur the development of new therapeutic means in the fight against human diseases such as obesity and its secondary complications, anorexia nervosa, ingestion and heart burn, and inflammatory bowel disease.